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Enhanced Route To Meta Substitution

Technique makes it possible to choose ortho or meta aromatic substitution at will

by Stu Borman
March 16, 2015 | A version of this story appeared in Volume 93, Issue 11

A reaction scheme showing enhanced meta substitution.

It is difficult to derivatize substituted aromatic rings selectively at the meta position—that is, two carbon atoms away from another substituent. Researchers have now developed an improved method for accomplishing that feat, and the approach is switchable in that it can also be used for ortho (one carbon away) substitution if two reagents are omitted (Nature 2015, DOI: 10.1038/nature14214). Jin-Quan Yu of Scripps Research Institute California and coworkers earlier developed a U-shaped palladium-based group that could be attached to an aromatic ring to direct bond breaking of a meta-C–H bond and insertion of a new group at that position (Nature 2012, DOI: 10.1038/nature11158; C&EN, July 2, 2012, page 9). But the directing group was complex and inconvenient. Now, they have devised a simpler system, in which Pd(II) catalyzes ortho substitution in aromatic rings with an amide directing group. Preliminary work indicates other directing groups may work as well. The substituent switches to the meta position when a pyridine ligand and norbornene are added. The method could be useful for diversifying drug candidates.


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